Translational Control in IPF

IPF 中的翻译控制

• 批准号: 8119476
• 负责人: Peter B Bitterman
• 金额: $ 41.97万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119476
• 关键词: Affect; Attention; Attenuated; Base Sequence; Binding Proteins; Binding Sites; Biologic Characteristic; Biological; Biology; Breast Carcinoma; Cancer Biology; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell division; Cells; Cessation of life; Chemicals; Cicatrix; Data; Disease; Elements; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Growth Factor; Growth Factor Receptors; Hamman-Rich syndrome; Health; Heart; Human; Informatics; Integumentary system; Kidney; Laboratory Study; Lead; Left; Lesion; Liver; Lung; Lung diseases; Malignant Neoplasms; Maps; MicroRNAs; Microarray Analysis; Molecular Target; Natural Immunity; Normal Cell; Ontology; Organ; Organ failure; Pathogenesis; Pathway interactions; Patients; Pattern; Physiological; Polyribosomes; Preparation; Property; Protein Biosynthesis; Proteins; Publications; RNA; RNA Binding; Refractory; Regulation; Regulatory Element; Report (document); Secure; Signal Transduction; Skin; Testing; Tissues; Transcript; Translation Initiation; Translations; adaptive immunity; base; cancer cell; chemokine; computerized data processing; cytokine; eicosanoid metabolism; human disease; novel; prototype; receptor; research study; response

DESCRIPTION (provided by applicant): Fibroproliferative disorders are common, progressive and refractory to available therapy. Fibroblasts derived from fibroproliferative lesions manifest an unexplained autonomy for growth and survival signals. In this revised proposal, we propose to study lung fibroblasts from patients with Idiopathic Pulmonary Fibrosis (IPF), a prototype fibroproliferative disease, and elucidate the mechanism of autonomous function using our recent discoveries in cancer biology as a guide. In studies of human breast carcinoma, we discovered that autonomy is conferred by deregulation of the cap-dependent translation initiation machinery, designated eIF4F. In normal cells, eIF4F receives signals from matrix and growth factor receptors and their downstream intermediates, and orchestrates these inputs into a physiological growth response. In cancer cells, eIF4F serves to integrate and amplify diverse growth and survival signals emanating from a plethora of growth-related genes to confer autonomy. Here we show preliminary data indicating that aberrant activation of eIF4F is a property of IPF fibroblasts; that activating eIF4F in fibroblasts stimulates cell cycle entry in the absence of growth factors; and that mice genetically engineered to lack negative regulators of eIF4F have an exaggerated fibrotic response. We therefore hypothesize that deregulated translational control of transcripts governing cell cycle transit lies on the causal pathway to fibrosis; and propose 2 specific aims to test this hypothesis: Specific Aim 1: Classify transcripts in IPF fibroblasts that display coordinate changes in translational efficiency into discrete groups based on shared chemical and biological characteristics. A. Chemical: Nucleotide sequences that comprise known or candidate RNA regulatory elements. B. Biological: Assigned function. Specific Aim 2: Focusing on transcripts encoding cell cycle regulators, determine whether disrupting regulatory element function attenuates IPF fibroblast proliferative autonomy. A. Known regulatory elements. B. Newly discovered regulatory elements. If successful, our studies will precisely identify derangements in the translational step of gene expression that confer IPF fibroblasts with proliferative autonomy, thus revealing new classes of molecular targets for antifibrotic therapy in the lung and other organs. PUBLIC HEALTH RELEVANCE. Many human diseases are characterized by scar tissue accumulation that leads to organ dysfunction and death. Scarring, also called fibrosis, can affect many different organs including the lung, liver, kidney, heart, vasculature and skin; and is often very difficult to treat. Here we propose to study the cell producing scar tissue, the fibroblast, in a deadly form of lung scarring that afflicts more than 35,000 people in the US, termed idiopathic pulmonary fibrosis (IPF). Our pilot experiments point to abnormal activation of the cellular machinery that produces protein, in a pattern similar to that seen in cancer. Our goal in this study is to understand how the biology of fibroblasts can be redirected by abnormalities in the protein synthesis machinery in a manner that leads to lung fibrosis. This information has the potential to lead to new treatments for all scarring diseases by revealing new molecular targets for antifibrotic therapy.

描述（由申请人提供）：纤维增生性疾病是常见的、进行性的并且现有疗法难以治愈。源自纤维增殖性病变的成纤维细胞表现出无法解释的生长和生存信号自主性。在这项修订后的提案中，我们建议研究特发性肺纤维化（IPF）（一种纤维增生性疾病的原型）患者的肺成纤维细胞，并以我们在癌症生物学方面的最新发现为指导，阐明自主功能的机制。在人类乳腺癌的研究中，我们发现自主性是通过解除对帽子依赖性翻译起始机制（称为 eIF4F）的管制而赋予的。在正常细胞中，eIF4F 接收来自基质和生长因子受体及其下游中间体的信号，并将这些输入协调成生理生长反应。在癌细胞中，eIF4F 用于整合和放大大量生长相关基因发出的不同生长和生存信号，以赋予其自主性。在这里，我们展示了初步数据，表明 eIF4F 的异常激活是 IPF 成纤维细胞的一个特性；在缺乏生长因子的情况下，激活成纤维细胞中的 eIF4F 可刺激细胞周期进入；经过基因工程改造，缺乏 eIF4F 负调节因子的小鼠会出现过度的纤维化反应。因此，我们假设控制细胞周期转运的转录本的翻译控制失调是纤维化的因果途径。并提出 2 个具体目标来检验这一假设： 具体目标 1：根据共同的化学和生物学特征，将 IPF 成纤维细胞中显示翻译效率坐标变化的转录物分类为离散组。 A. 化学：包含已知或候选 RNA 调节元件的核苷酸序列。 B. 生物：指定的功能。具体目标 2：关注编码细胞周期调节因子的转录本，确定破坏调节元件功能是否会减弱 IPF 成纤维细胞增殖自主性。 A. 已知的监管要素。 B. 新发现的调控元件。如果成功，我们的研究将精确识别基因表达翻译步骤中的紊乱，从而赋予 IPF 成纤维细胞增殖自主权，从而揭示肺部和其他器官抗纤维化治疗的新分子靶点。公共卫生相关性。许多人类疾病的特点是疤痕组织堆积，导致器官功能障碍和死亡。疤痕也称为纤维化，会影响许多不同的器官，包括肺、肝、肾、心脏、脉管系统和皮肤；并且通常很难治疗。在这里，我们建议研究产生疤痕组织的细胞，即成纤维细胞，这种致命的肺部疤痕形式困扰着美国超过 35,000 人，称为特发性肺纤维化 (IPF)。我们的初步实验表明，产生蛋白质的细胞机器异常激活，其模式与癌症中所见的模式相似。我们在这项研究中的目标是了解成纤维细胞的生物学如何通过蛋白质合成机制的异常而改变方向，从而导致肺纤维化。该信息有可能通过揭示抗纤维化治疗的新分子靶标，为所有疤痕疾病带来新的治疗方法。

项目成果

Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.

• DOI: 10.1038/cgt.2012.39
• 发表时间: 2012-09
• 期刊: Cancer gene therapy
• 影响因子: 6.4

NF-kappaB mediates the survival of human bronchial epithelial cells exposed to cigarette smoke extract.

NF-kappaB 介导暴露于香烟烟雾提取物的人支气管上皮细胞的存活。

• DOI: 10.1186/1465-9921-9-66
• 发表时间: 2008-09-23
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Liu X;Togo S;Al-Mugotir M;Kim H;Fang Q;Kobayashi T;Wang X;Mao L;Bitterman P;Rennard S
• 通讯作者: Rennard S

Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.

• DOI: 10.1513/pats.201012-067cb
• 发表时间: 2011-06-01
• 期刊: Proceedings of the American Thoracic Society
• 作者: Borok, Zea;Whitsett, Jeffrey A;Hoshizaki, Deborah
• 通讯作者: Hoshizaki, Deborah

Effect of asymmetric dimethylarginine (ADMA) on heart failure development.

非对称二甲基金融蛋白（ADMA）对心力衰竭发育的影响。

• DOI: 10.1016/j.niox.2016.02.006
• 发表时间: 2016-04-01
• 期刊: NITRIC OXIDE-BIOLOGY AND CHEMISTRY
• 影响因子: 3.9
• 作者: Liu, Xiaoyu;Hou, Lei;Xu, Dachun;Chen, Angela;Yang, Liuqing;Zhuang, Yan;Xu, Yawei;Fassett, John T.;Chen, Yingjie
• 通讯作者: Chen, Yingjie

Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma.

• DOI: 10.1038/sj.bjc.6605184
• 发表时间: 2009-08-04
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Jacobson BA;De A;Kratzke MG;Patel MR;Jay-Dixon J;Whitson BA;Sadiq AA;Bitterman PB;Polunovsky VA;Kratzke RA
• 通讯作者: Kratzke RA